Risk Of Severe Bacterial Infections Research Articles

Depletion of Lachnospiraceae Marks the Development of Antibiotic-Associated Neutropenia in Pediatric Patients

Prolonged antibiotic administration has been associated with peripheral cytopenias in up to 10-15% of patients. Of these, neutropenia is particularly notable because of the associated risk of severe bacterial infections. Yet, the mechanisms underlying antibiotic-associated neutropenia remain poorly understood. Recent studies in murine models demonstrate that antibiotics suppress hematopoiesis by depletion of the intestinal microbiota, with concomitant suppression of basal Type I interferon (IFN) and STAT1 signaling. Oral administration of the microbial metabolites that induce Type I IFN restores normal hematopoiesis in antibiotic-treated mice. These findings support a paradigm in which products of the intestinal microbiota enter the bloodstream and travel to the bone marrow where they promote production of growth cytokines that support normal hematopoiesis. To identify microbiota and microbiota-derived metabolites altered in patients with antibiotic-associated neutropenia, we enrolled pediatric patients receiving antibiotic therapy for a planned duration of fourteen days or more in a multicenter-IRB approved study. We analyzed pre- and post-treatment stool samples from 51 subjects by 16S rRNA sequencing and untargeted metabolomics profiling. Neutropenia occurred in 13% of prospectively enrolled subjects. In total, 10 neutropenic patients were included in the study, with 29 control patients selected by frequency matching for age, race, and ethnicity. Length of intravenous antibiotic treatment, total length of antibiotic treatment, length of stay and admission to the intensive care unit were correlated with the development of neutropenia, whereas type of antibiotic or type of infection were not. Based on 16S rRNA sequencing, alpha diversity was significantly decreased in the stool of patients with neutropenia but not in controls (p= 0.027 vs p= 0.059). Analysis of taxa abundance showed significant depletion of Lachnospiraceae in patients with neutropenia (p=0.043), while no significant difference was identified in controls. Lachnospiraceae are a main producer of short chain fatty acids and have been linked to hematopoietic stem cell transplant outcomes. Partial least square-discriminant analysis (sPLS-DA) showed that the metabolomes of neutropenic and control stools were similar at baseline. However, 17 metabolites were differentially abundant after antibiotic treatment in the neutropenic group but not in the control group including citrulline, tyrosine, and N-acetylglucosamine/N-acetylgalactosamine. Future work will assess whether these compounds can rescue antibiotic-associated neutropenia in the animal model. This is the first clinical study linking changes in the intestinal microbiota with antibiotic associated neutropenia. An improved understanding of the molecular mechanisms by which the microbiome sustains normal hematopoiesis will lead to ways to prevent and treat antibiotic-associated bone marrow suppression.

Molecular and Clinical Data of Antimicrobial Resistance in Microorganisms Producing Bacteremia in a Multicentric Cohort of Patients with Cancer in a Latin American Country.

Patients with cancer have a higher risk of severe bacterial infections. This study aims to determine the frequency, susceptibility profiles, and resistance genes of bacterial species involved in bacteremia, as well as risk factors associated with mortality in cancer patients in Colombia. In this prospective multicenter cohort study of adult patients with cancer and bacteremia, susceptibility testing was performed and selected resistance genes were identified. A multivariate regression analysis was carried out for the identification of risk factors for mortality. In 195 patients, 206 microorganisms were isolated. Gram-negative bacteria were more frequently found, in 142 cases (68.9%): 67 Escherichia coli (32.5%), 36 Klebsiella pneumoniae (17.4%), and 21 Pseudomonas aeruginosa (10.1%), and 18 other Gram-negative isolates (8.7%). Staphylococcus aureus represented 12.4% (n = 25). Among the isolates, resistance to at least one antibiotic was identified in 63% of them. Genes coding for extended-spectrum beta-lactamases and carbapenemases, blaCTX-M and blaKPC, respectively, were commonly found. Mortality rate was 25.6% and it was lower in those with adequate empirical antibiotic treatment (22.0% vs. 45.2%, OR: 0.26, 95% CI: 0.1-0.63, in the multivariate model). In Colombia, in patients with cancer and bacteremia, bacteria have a high resistance profile to beta-lactams, with a high incidence of extended-spectrum beta-lactamases and carbapenemases. Adequate empirical treatment diminishes mortality, and empirical selection of treatment in this environment of high resistance is of key importance.

Congenital asplenia study: clinical and laboratory characterisation of adults with congenital asplenia.

Congenital asplenia is a rare disorder commonly associated with other visceral and cardiac congenital anomalies. Isolated congenital asplenia is even less common than syndromic forms. The risk of severe bacterial infections associated with asplenia is the most concerning clinical implication and carries a significant mortality risk. Prophylactic measures against the clinical syndrome known as overwhelming postsplenectomy infections (OPSI) include vaccination, prophylactic and emergency antibiotics and health education including fever management and travel advice. This case series describes fourteen adults with congenital asplenia and polysplenia syndrome, most of whom were diagnosed incidentally as adults, and outlines the nature of their diagnosis, clinical phenotype, family history and key pathology findings.

The risk of severe bacterial infection in non-transfusion-dependent thalassemia.

The risk of severe bacterial infection in non-transfusion-dependent thalassemia.

Risk-score based strategy to minimize antibiotic exposure in children with sickle cell disease and fever

Severe bacterial infections (SBI) have become less frequent in children with sickle cell disease (SCD) in the last decades. However, because of their potential risk of SBI, they usually receive empirical therapy with broad-spectrum antibiotics when they develop fever and are hospitalized in many cases. We performed a prospective study including 79 SCD patients with fever [median age 4.1 (1.7–7.5) years, 78.5% males; 17 of the episodes were diagnosed with SBI and 4 of them were confirmed] and developed a risk score for the prediction of SBI. The optimal score included CRP > 3 mg/dl, IL-6 > 125 pg/ml and hypoxemia, with an AUC of 0.91 (0.83–0.96) for the prediction of confirmed SBI and 0.86 (0.77–0.93) for possible SBI. We classified the patients in 3 groups: low, intermediate and high risk of SBI. Our risk-score-based management proposal could help to safely minimize antibiotic treatments and hospital admissions in children with SCD at low risk of SBI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s15010-021-01702-w.

Infections in secondary immunodeficiency patients treated with Privigen® or Hizentra®: a retrospective US administrative claims study in patients with hematological malignancies

B cell-derived lymphoproliferative disorders are associated with secondary immunodeficiency (SID); some patients require immunoglobulin replacement therapy (IgRT) to mitigate infections. Using IQVIA’s PharMetrics® Plus database, patients with SID who received IgPro10/IgPro20 in the 12 months post-diagnosis (IgRT users) were matched to patients with SID not receiving IgRT (non-IgRT users). The risk of severe infection was compared using within-patient change from baseline to follow-up as well as between cohorts. Overall, 277 IgRT users were matched to 1019 non-IgRT users. Before IgRT, more IgRT users experienced any bacterial infection (88.4% vs. 72.9%; p<.0001) or ≥1 severe bacterial infection (SBI) (42.2% vs. 31.8%; p=.0011) vs. non-IgRT users. During follow-up, risk of SBI among IgRT users (21.7%) reached parity with non-IgRT users (21.2%). IgRT was associated with a reduction in SBIs to levels comparable with the lower ‘baseline infection risk’ of non-IgRT users. These criteria help define SID patients who may benefit from IgRT.

Relationship between influenza and dengue outbreaks, and subsequent bacterial sepsis in French Guiana: A time series analysis.

Background: Influenza has been shown to increase the risk for severe bacterial infection, in the tropics the seasonality of influenza epidemics is less marked, and this may not be the case. Dengue is often followed by prolonged asthenia and some physicians hypothesized increased susceptibility to infections based on anecdotal observations.Design and Methods: Time series of influenza and dengue surveillance were confronted bacterial sepsis admissions to test the hypotheses. Monthly surveillance data on influenza and dengue and aggregated sepsis data in Cayenne hospital were matched between 24/10/2007 and 27/09/2016. An ARIMA (1,0,1) model was used.Results The series of the number of monthly cases of sepsis was positively associated with the monthly number of cases of influenza at time t (β=0.001, p=0.0359). Forecasts were imperfectly correlated with sepsis since influenza is not the only risk factor for sepsis. None of the ARIMA models showed a significant link between the dengue series and the sepsis series.Conclusions: There was thus no link between dengue epidemics and sepsis, but it was estimated that for every 1,000 cases of flu there was one additional case of sepsis. In this tropical setting, influenza was highly seasonal, and improved vaccination coverage could have benefits on sepsis.Significance for public healthSimultaneous infections may have complex consequences ranging from synergistic, neutral or antagonistic. Dengue fever and influenza cause repeated epidemics and may have consequences on the host’s immune response. Hypothesizing that an infection by dengue or influenza could increase the risk of bacterial infection we showed that there was no relation between dengue and sepsis, but that there was a relation between influenza and sepsis. Despite the tropical setting of French Guiana, the highly seasonal pattern of influenza suggests the vaccine reimbursement window should be extended.

Statin use and risk of severe bacterial infection in a population living with HIV: prospective cohort study of the ANRS CO3 Aquitaine Cohort 2000–2018

ObjectivesBacterial infections remain one of the main causes of morbidity and death in people living with HIV (PLHIV) in the most recent years. Several studies have demonstrated a protective effect of statins in the primary prevention of bacterial infections in other immunocompromised populations, but this effect remains controversial. The objective of this study was to evaluate the effect of statin use on the occurrence of a first episode of severe bacterial infection (SBI) in PLHIV in the ANRS CO3 Aquitaine cohort between 2000 and 2018. MethodsAll individuals included in the prospective ANRS CO3 Aquitaine cohort who had at least two follow-up visits between 2000 and 2018 were included. The primary endpoint was the occurrence of a first episode of bacterial infection leading to hospitalization of ≥48 hours or death. Statin exposure was updated during follow-up. Marginal Cox structural models were developed to consider the potential indication bias and time-dependent confusion. Numerous sensitivity analyses were carried out. ResultsIn this study 51 658 person-years were followed. The overall incidence of a first episode of SBI was 12.4/1000 person-years. No effect of statins on the occurrence of SBI was demonstrated when subjects were considered on statins throughout their follow-up after treatment initiation (HR = 0.97; 95%CI: 0.75–1.25). The results were similar for the effect of statins on the risk of pneumonia and for all sensitivity analyses. ConclusionIn this large cohort of PLHIV with 18 years of follow-up and a high risk of severe infections, we found no effect of statins on the risk of occurrence of SBI or pneumonia.

Incidence and treatment costs of severe bacterial infections among people who inject heroin: A cohort study in South London, England

BackgroundPeople who inject drugs often get bacterial infections. Few longitudinal studies have reported the incidence and treatment costs of these infections. MethodsFor a cohort of 2335 people who inject heroin entering treatment for drug dependence between 2006 and 2017 in London, England, we reported the rates of hospitalisation or death with primary causes of cutaneous abscess, cellulitis, phlebitis, septicaemia, osteomyelitis, septic arthritis, endocarditis, or necrotising fasciitis. We compared these rates to the general population. We also used NHS reference costs to calculate the cost of admissions. ResultsDuring a median of 8.0 years of follow-up, 24 % of patients (570/2335) had a severe bacterial infection, most commonly presenting with cutaneous abscesses or cellulitis. Bacterial infections accounted for 13 % of all hospital admissions. The rate was 73 per 1000 person-years (95 % CI 69–77); 50 times the general population, and the rate remained high throughout follow-up. The rate of severe bacterial infections for women was 1.50 (95 % CI 1.32–1.69) times the rate for men. The mean cost per admission was £4980, and we estimate that the annual cost of hospital treatment for people who inject heroin in London is £4.5 million. ConclusionsPeople who inject heroin have extreme and long-term risk of severe bacterial infections.

Risk of Severe Bacterial Infection in People Living Human Immunodeficiency Virus Infection in the Combined Antiretroviral Therapy Era.

Severe bacterial infections are the first cause of morbidity in people with human immunodeficiency virus (PWH). We aimed to assess their incidence and to analyze their determinants. We studied human immunodeficiency virus (HIV)-1-infected individuals aged at least 15 years and prospectively followed between 2006 and 2015 in the French Hospital Database on HIV. The Andersen and Gill model was used to calculate the adjusted hazard ratios (HRs), focusing on heavy alcohol use and neutrophil function-altering comorbidities. Of 25 795 participants, 1414 developed 1883 severe bacterial infections. Between 2006 and 2009 and 2013 and 2015, the incidence fell from 13.2 (95% confidence interval [CI], 12.3-14.1) to 7.1 (95% CI, 6.3-7.8) per 1000 person-years. Heavy alcohol use was associated with an increased risk of severe bacterial infection (HR = 1.3, 95% CI = 1.1-1.7 for 40-80 g/day and HR = 1.6, 95% CI = 1.2-2.1 for >80 g/day), as were diabetes, chronic kidney disease, and end-stage liver disease (HR = 1.2, 95% CI = 1.0-1.4 when 1 comorbidity; HR = 2.3, 95% CI = 1.6-3.4 when more than 1 comorbidity), and nonacquired immune deficiency syndrome-defining malignancy (HR = 2.0; 95% CI, 1.6-2.4). Heavy alcohol use was associated with an increased risk of severe bacterial infection, as were neutrophil function-altering comorbidities. Controlled-drinking approaches should be promoted and comorbidity management should be strengthened in PWH.

Memory B lymphocytes in peripheral blood in coeliac disease: a pilot study

Functional hyposplenism is a condition accompanying many diseases including autoimmune disorders and lymphomas. Hyposplenism is also commonly found in adult coeliac disease (up to 20 % of non-complicated and up to 80 % of complicated disease). Hyposplenism is associated with an increased risk of severe infections ( Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae ). The aim of this prospective study was to investigate memory B lymphocytes as an indirect biomarker of functional hyposplenism. A total of 42 patients with coeliac disease (11 men, 31 women; mean age 49±14 years) and 10 healthy controls, blood donors (2 men, 8 women; mean age 39±7 years) were enrolled into the study. Nobody underwent previous splenectomy and no individual suffered from immunodeficiency. The DuraClone IM panel was used to identify B lymphocytes subpopulations in peripheral blood samples by flow cytometry Navios (Beckman Coulter) with software analysis using Kaluza version 1.2. Patients with coeliac disease and controls did not differ in basic parameters of leukocyte and total lymphocyte blood count. Switched memory B lymphocytes (CD19+CD27+IgD-), non-switched memory / marginal-zone-like B lymphocytes (CD19+CD27+IgD+) and IgM memory B lymphocytes (CD19+CD27+IgM++) were significantly lower in coeliac disease compared to controls. Follicular (naive) B lymphocytes were not significantly different between coeliac disease and controls. In conclusion, dysfunction of memory B lymphocytes can be responsible for an increased risk of severe bacterial infections in coeliac disease. Patients with coeliac disease with dysfunction of memory B lymphocytes are clearly indicated for anti-pneumococcal vaccination.

PS1154 INFECTIONS IN CLL PATIENTS RECEIVING IBRUTINIB: INCIDENCE AND PREDISPOSING FACTORS

Background:Infections are a typical complication of chronic lymphocytic leukemia (CLL). Guidelines for prevention of infections in patients with CLL receiving ibrutinib is lacking, possibly due to a paucity of data in the literature.Aims:To analyze factors associated with severe bacterial, viral and fungal infections in CLL patients receiving ibrutinib.Methods:Data on bacterial, viral and fungal infections in CLL patients, who received ibrutinib during 3,6‐year period from May 2015 to December 2018 in a single centre are presented. Infections were graded according to CTCAE criteria, version IV. Cumulative incidences of infections were estimated according to Kaplan‐Meier and comparison between groups was performed using Hazard Ratios and CIs obtained from Cox regression models.Results:The study included 240 CLL patients. The median age was 65 years (range 32–91 years), 154 (64%) were male, 117 (48%) had stage C, 65 (27%) had ECOG status ≥ 2. Two hundred four patients (85%) received ibrutinib as monotherapy, 36 (15%) along with monoclonal antibodies to CD20. The median follow‐up was 14.8 months (range 1 ‐ 44 months). Most patients (224, 93%) received ibrutinib for relapse with a median number of previous treatment lines of 3 (range 1–12). Neutropenia (defined as &lt;1000 cells/mkl) prior to ibrutinib was found in 20 patients (8%). Steroid hormones were given to 20 patients. A total of 525 infectious episodes were recorded in 183 patients. Of these, 381 (72.5%) episodes were bacterial/mixed infections, 115 (22%) viral and 29 (5.5%) fungal infections. Among bacterial infections 121 (32%) were scored as grade III, 43 (11%) as grade IV and 7 (1,8%) infections were fatal. The overall cumulative incidence of grade III‐V bacterial infections during 12 months was 37% (95% CI 31–43%), viral infections ‐ 28% (95% CI 22–34), and fungal infections 8% (95% CI 4–12). There was a significantly (p &lt; .05) higher cumulative incidence of grade III‐V bacterial infections in patients with ≥3 lines of prior therapy (HR: 2.0; 95% CI 1.36–2.97), Binet stage C (HR: 1.4; 95% CI 0.95–2.08), ECOG ≥ 2 (HR: 2.4; 95% CI 1.6–3.6), baseline neutropenia (HR: 1.25; 95% CI 0.73–2.13), as well as in males (HR: 1.8; 95% CI 1.16–2.8, p = 0.004). In a multivariate analysis male gender (RR 1.89, 95% CI 0.5–3, p = 0.006), ECOG ≥ 2 (RR = 1.97, 95% CI 0.5–3) and initial neutropenia (RR = 1.76, 95% CI 0.99–3.1) were significant and independent risk factors. Cumulative incidence of any fungal infections was associated with simultaneous use of corticosteroids (HR: 6; 95% CI 5.85–14,7) and baseline neutropenia (HR: 2.36; 95% CI 0.95–5.85). The only parameter significantly associated with viral infections was ≥3 lines of prior therapy (HR: 1.74; 95% CI 1.06–2.86). As 160 (87%) patients experienced &gt;1 episode of infections, we compared rates of infections expressed as number per 100 patient‐months. Grade III‐V bacterial infections were significantly associated with ≥3 lines of previous therapy (3,6 vs 2,3), ECOG ≥ 2 (5,72 vs 2,27), male gender (3,2 vs 2,03) and stage C (3,8 vs 2,24). Fungal infections were more frequently observed in patients with a history of &gt;3 lines of treatment (0,87 vs 0,31), initial neutropenia (1,75 vs 0,47), simultaneous use of steroids (1,96 vs 0,39).Summary/Conclusion:Patients with ECOG status &gt;2 and initial neutropenia are at highest risk of severe bacterial infections and may benefit from antibacterial prophylaxis. Antifungal prophylaxis can be considered in patients who receive corticosteroid hormones simultaneously with ibrutinib

Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors

Background. Infections are a common complication of chronic lymphocytic leukemia (CLL). The lack of recommendations for infection prevention in CLL patients treated with ibrutinib can be attributed by an insufficiency of data in the literature. Aim. To assess the incidence and nature of infections in CLL patients treated with ibrutinib and to analyze predisposing factors. Materials &amp; Methods. The paper provides data on bacterial, viral, and fungal infections in CLL patients treated with ibrutinib for 4.2 years (November 2014 to December 2018) in a single center. Severity grade was determined according to CTCAE criteria (version 4). Results. The trial included 240 CLL patients. Median age was 65 years (range 32-91), 86 (36 %) patients were female, and 117 (48 %) patients had Binet stage C. Ibrutinib as monotherapy was administered to 204 (85 %) patients, 36 (15 %) patients received it in combination with monoclonal anti-CD20 antibodies. Median follow-up was 14.8 months (range 1-54). Most patients (n = 224, 93 %) received ibrutinib for relapsed CLL. Median number of prior therapy lines was 3 (range 1-12). Neutropenia (specified as neutrophil level &lt; 1000 cells/μL) before ibrutinib treatment was identified in 20 (8 %) patients. Glucocorticoid hormones (GCs) together with ibrutinib were administered to 20 patients. A total of 525 infectious episodes were registered in 183 patients. Out of them 381 (72.5 %) were bacterial/mixed, 115 (22 %) were viral, and 29 (5.5 %) were fungal infections. Among bacterial/mixed infections 121 (32 %) episodes were qualified as infection of grade 3 and 43 (11 %) episodes were qualified as grade 4. In 7 (1.8 %) patients infections were fatal. Within 12 months overall cumulative incidence of bacterial infections of grade 3/4 was 37 % (95% confidence interval [95% CI] 31-43 %), as for viral infections it was 28 % (95% CI 2234 %), and as for fungal infections it was 8 % (95% CI 4-12 %). Higher cumulative incidence of bacterial infections of grade 3/4 was identified in patients with &gt; 3 lines of therapy before ibrutinib treatment (hazard ratio [HR] 2.0; 95% CI 1.36-2.97), with Binet stage C (HR 1.4; 95% CI 0.95-2.08), with ECOG status &gt; 2 (HR 2.4; 95% CI 1.6-3.6), baseline neutropenia (HR 1.25; 95% CI 0.73-2.13), as well as in men (HR 1.8; 95% CI 1.16-2.8; p = 0.004). Multivariate analysis showed that male sex (HR 1.89; 95% CI 0.5-3.0; p = 0.006), ECOG status &gt; 2 (HR 1.97; 95% CI 0.5-3.0), and baseline neutropenia (HR 1.76; 95% CI 0.99-3.1) were significant and independent risk factors. Cumulative incidence of any fungal infection was associated with simultaneous use of GCs (HR 6.0; 95% CI 5.85-14.7) and baseline neutropenia (HR 2.36; 95% CI 0.95-5.85). The only parameter significantly associated with viral infections was the number of prior therapy lines &gt; 3 (HR 1.74; 95% CI 1.06-2.86; p = 0.029). Conclusion. Patients with baseline neutropenia and ECOG status &gt; 2 face the highest risk of severe bacterial infections. We believe that antibacterial prophylaxis should be considered in such patients till ECOG status becomes &lt; 2 and neutropenia resolves. Patients receiving GCs together with ibrutinib face the risk of fungal infections at any stage of treatment. In these patients the simultaneous antifungal prophylaxis should be considered.

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

BackgroundCotrimoxazole (CTX) preventive therapy (CPT) reduces opportunistic infections and malaria in HIV-infected patients. In Africa, policies on sustained CPT during antiretroviral therapy (ART) differ between countries. We assessed the safety of discontinuing CPT in stable patients on ART in Uganda.MethodsCOSTOP was a double-blind placebo-controlled trial. Patients aged ≥18 years, on CPT, and stable on ART (CD4 counts ≥250 cells/μL); were randomised to daily oral placebo (PLC group) or cotrimoxazole 960 mg/tablet (CTX group). Co-primary outcomes were: (i) time to first cotrimoxazole-preventable infection, with non- inferiority of PLC defined as the upper one-sided 95% confidence limit of the adjusted hazard ratio(aHR) ≤1.25; and (ii) time to first grade 3/4 haematological adverse event.Findings2180 subjects (1091 PLC; 1089 CTX) were enrolled. 932 PLC and 943 CTX completed the trial after 12 months minimum follow up. Ninety-eight participants (59 PLC; 39 CTX) experienced 120 cotrimoxazole- preventable events, mainly bacterial pneumonia (72 events, 4 deaths PLC); (48 events, 2 deaths CTX). The aHR for time to first event was 1.57 (upper one-sided 95% confidence limit 2.21) in per protocol population (similar results in ITT population). 551 participants (318 CTX; 233 PLC) experienced 1043 haematological adverse events (616 CTX; 427 PLC). Time to the first adverse event, mainly neutropenia, was shorter in the CTX group (aHR 0.70 95%CI 0.59–0.82; log-rank χ2 = 18.08; P<0.0001). 362 (276 PLC, 86 CTX) participants experienced at least one episode of confirmed clinical malaria (P<0.0001).InterpretationIn ART stable patients with CD4 counts ≥250 cells/μL, continued CPT significantly reduces risk of severe bacterial infections and protects against malaria, while discontinuing CPT reduces haematological adverse events.

Approach to Neonates and Young Infants with Fever without a Source Who Are at Risk for Severe Bacterial Infection.

Introduction Among neonates and infants <3 months of age with fever without a source (FWS), 5% to 15% of cases are patients with fever caused by a serious bacterial infection (SBI). To favour the differentiation between low- and high-risk infants, several algorithms based on analytical and clinical parameters have been developed. The aim of this review is to describe the management of young infants with FWS and to discuss the impact of recent knowledge regarding FWS management on clinical practice. Materials and Methods PubMed was used to search for all of the studies published over the last 35 years using the keywords: “fever without source” or “fever of unknown origin” or “meningitis” or “sepsis” or “urinary tract infection” and “neonate” or “newborn” or “infant <90 days of life” or “infant <3 months”. Results and Discussion The selection of neonates and young infants who are <3 months old with FWS who are at risk for SBI remains a problem without a definitive solution. The old Rochester criteria remain effective for identifying young infants between 29 and 60 days old who do not have severe bacterial infections (SBIs). However, the addition of laboratory tests such as C-reactive protein (CRP) and procalcitonin (PCT) can significantly improve the identification of children with SBI. The approach in evaluating neonates is significantly more complicated, as their risk of SBIs, including bacteremia and meningitis, remains relevant and none of the suggested approaches can reduce the risk of dramatic mistakes. In both groups, the best antibiotic must be carefully selected considering the clinical findings, the laboratory data, the changing epidemiology, and increasing antibiotic resistance of the most common infectious bacteria.

Outcomes of Immunocompetent Children Presenting with Fever and Neutropenia

BackgroundNeutropenia may alarm clinicians and prompt extensive evaluation in children with fever, even in immunocompetent patients. ObjectiveOur aim was to determine outcomes in previously healthy febrile children presenting to the emergency department with severe neutropenia. MethodsWe reviewed data from infants and children aged 3–36 months with fever and severe neutropenia, defined as a peripheral neutrophil count <500 × 103/μL, at our institution between January 1, 2012 and December 31, 2015. We compared our results to those from a similar study of children with a peripheral neutrophil count of 500–1000 × 103/μL. ResultsSevere neutropenia was recorded in 52 patients; severe bacterial infection (SBI) was found in 1 (1.9%), but none had a positive blood culture. Incidence of SBI was not different from that found in a study of similar patients with moderate neutropenia. ConclusionsImmunocompetent patients with fever and severe neutropenia do not carry a higher risk for SBI compared to patients with fever and moderate neutropenia. Such patients could potentially be followed closely with serial blood counts to ensure bone marrow recovery, without the use of antibiotics.

How I manage children with neutropenia.

Neutropenia, usually defined as a blood neutrophil count <1·5×109 /l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony-stimulating factor to treat childhood neutropenia.

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial

SummaryBackgroundThe effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial.MethodsThe START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048.FindingsPatients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26–0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71–0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50–1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately.InterpretationImmediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.FundingNational Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

THU-432 - Donor mannose-binding lectingene polymorphisms increase the risk of severe bacterial infections after liver transplantation

THU-432 - Donor mannose-binding lectingene polymorphisms increase the risk of severe bacterial infections after liver transplantation

Orbital cellulitis in a child with sickle cell anemia

PurposeOrbital cellulitis and preseptal cellulitis are the major infections of the ocular adnexal and orbital tissues. Orbital cellulitis is an infection of the soft tissues of the orbit, posterior to the orbital septum.The purpose of this text is to point out sickle‐cell disease as an important risk factor in a 2‐year‐old boy with sinusitis.MethodsWe evaluated a 2‐year‐old boy with sickle‐cell disease and sinusitis treated with oral amoxicillin (80 mg/kg/day). He presented a remarkable proptosis, intense ophthalmoplegia and conjunctival chemosis, with a temperature of 39°C and leukocytosis with left shift. We treated him with clindamycin 30 mg/kg, cefotaxime 200 mg/kg and prednisolone IV.ResultsAxial image CT scan demonstrated sinusitis of the left ethmoid sinus. Furthermore, there was a left sided subperiosteal abscess between the medial wall of the left orbit and the left medial rectus muscle. Due to the bad evolution and the CT scan image, the sinus was drainage in a surgical procedure under general anesthesia. Appropriate patient evolution was achieved without the need for additional therapy.ConclusionsPatients with sickle‐cell anemia show anincreased risk of severe bacterial infections due to loss of functioning spleen tissue. Daily penicillin prophylaxis is the most commonly used treatment during childhood. Orbital cellulitis can result in orbital and intracranial complications. Blindness may occur secondary to elevated intraorbital pressure. This is the reason we must control the patient at least daily and evaluate the antibiogram. Finally, when medical treatment is not working and there is an elevated intraorbital pressure with involvement of the eyeball, the surgery cannot be postponed.